Parkinson’s disease is caused by an imbalance in the brain resulting from alpha-synuclein, a small unstable protein that misfolds and accumulates in clusters and clumps that destroy the brain cells of people with the disease. Researchers have now discovered that extracts from Damask roses and Koroneiki olives can prevent aggregates from forming. Future research will show whether one or more substances causes the beneficial effects, so that researchers can extract the beneficial compounds and avoid those with side-effects.
As humans age, some of the body’s sensitive balances shift, causing small errors to arise. One frequent and serious error in the brain occurs when proteins change their three-dimensional structure so that they clump together or aggregate. This occurs in such diseases as Parkinson’s and Alzheimer’s. Plants do not face the same challenges. They have a defence system that enables them to keep their proteins intact and healthy throughout life. A research group is now on the trail of this defence system.
“We have previously shown that plants are amazing treasure troves for compounds that prevent the aggregation of proteins. In our latest study, we examined Damask roses, since extracts from this plant have been used to treat Parkinson’s. The problem is that the extracts obtained have side-effects, so to investigate whether the plant has compounds that can prevent the alpha-synuclein folding, we fractionated the extract and found a fraction that inhibited the formation of the destructive protein clusters. The effect was stronger than what we found last year when we examined olives. Now we are trying to find out exactly which compound or compounds have the beneficial effect and understand why this prevents Parkinson’s from developing,” explains Daniel E. Otzen, Professor, Interdisciplinary Nanoscience Center (iNANO), Aarhus University.
Like wildfire through the cells
Damask roses (Rosa damascena) are known as the king of flowers in countries such as Iran and Greece, where rose water, essential oils and petals have been widely used in food, perfumes and medicine for many years. New studies have also shown that some of the compounds from Damask roses have antidepressant and anti-inflammatory properties and may also counteract bacteria, cancer and Alzheimer’s.
“These many promising properties, combined with the fact that plants do not have this accumulation of these misfolded proteins, inspired us to investigate whether extracts from Damask roses could also be used to treat people with Parkinson’s,” says Daniel Otzen.
However, the researchers were also aware of the various side-effects these rose extracts can have. Separating the positive effects from the negative ones could solve these problems. The researchers successfully achieved this by using ultra high-performance liquid chromatography, which separates compounds according to how much they bind to a specific material.
“This enabled us to separate the extract into 26 fractions. We then tested each individual fraction according to its ability to prevent alpha-synuclein from beginning to misfold and clump together. One fraction had an especially great preventive effect, and we analysed it more closely together with Jane Ward at Rothamsted Research in the United Kingdom and found four compounds: gallic acid, kaempferol glucoside, kaempferol rutinoside and quercetin,” explains co-corresponding author, Hossein Mohammad-Beigi, Postdoctoral Fellow, also from iNANO, who initiated the study.
The researchers tested the four compounds individually and found that all four had beneficial effects – both preventing the formation of fibrils of alpha-synuclein and, even more importantly, oligomers. These small soluble complexes of alpha-synuclein are believed to be the most harmful species in Parkinson’s, since they have been shown to bind with proteins such as tau in neurons’ cell membranes, eliminating the vital transport of ions across the membrane.
“When neurons degenerate, they can spread the toxic contents, and this can spread like wildfire from cell to cell. We therefore also tried to test the compounds on a human cell line in the laboratory and found no immediate toxic effects on the cells. The compounds reduced the number of harmful fibrils and oligomers, but perhaps most importantly and most surprisingly, the compounds reduced the harmful effects of the oligomers present,” says Hossein Mohammad-Beigi.
Queen of the olives
However, it is still too early to conclude that these new promising studies will lead to an actual cure for Parkinson’s. Initially, the researchers need to understand whether the individual compounds or combining compounds ensure the beneficial effects and, in addition, how the compounds prevent the formation and the harmful effects of alpha-synuclein oligomers that drive Parkinson’s. The researchers are especially examining polyphenols.
“Last year we screened 15 varieties of olives to identify compounds that can inhibit alpha-synuclein aggregation and oligomer toxicity and found a variety, Koroneiki, that caused the same inhibition, albeit slightly less powerfully,” explains Hossein Mohammad-Beigi.
Koroneiki is also called the queen of olives, but time will tell whether one of the polyphenols from Koroneiki or one of the compounds from the king of flowers, Damask rose, will be the strongest inhibitor of alpha-synuclein aggregation and oligomer toxicity. In any case, the researchers are now convinced that the plant universe is a regular treasure trove of beneficial compounds that can help us tremendously in combating degenerative brain diseases and other diseases.
“These plant products and their extracts are more prevalent in the diet in Mediterranean countries, and this is probably one reason for the lower incidence of these diseases. If we can learn to understand the mechanism behind the extracts and how they protect plants, animals and humans, the results can be really useful – for developing both beneficial diets and effective drugs,” concludes Daniel Otzen.
“Inhibitors of α-synuclein fibrillation and oligomer toxicity in Rosa damascena: the all-pervading powers of flavonoids and phenolic glycosides” has been published in ACS Chemical Neuroscience.
“Oleuropein derivatives from olive fruit extracts reduce α-synuclein fibrillation and oligomer toxicity” has been published in the Journal of Biological Chemistry.
Daniel Otzen’s group also showed in "A Possible Connection Between Plant Longevity and the Absence of Protein Fibrillation: Basis for Identifying Aggregation Inhibitors in Plants" has been published in Frontiers in Plant Science how plants in general are able to suppress protein aggregation.
In 2017, the Novo Nordisk Foundation awarded a grant to Daniel Otzen for the project Specific Binders Crossing the Blood–brain Barrier to Diagnose and Combat Parkinson’s Disease.